EP0019730B1 - Antimycotic agent, process for its preparation - Google Patents

Antimycotic agent, process for its preparation Download PDF

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Publication number
EP0019730B1
EP0019730B1 EP80102288A EP80102288A EP0019730B1 EP 0019730 B1 EP0019730 B1 EP 0019730B1 EP 80102288 A EP80102288 A EP 80102288A EP 80102288 A EP80102288 A EP 80102288A EP 0019730 B1 EP0019730 B1 EP 0019730B1
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EP
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Prior art keywords
antimycotic agent
general formula
agent according
imidazol
dimethyl
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EP80102288A
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German (de)
French (fr)
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EP0019730A1 (en
Inventor
Wolfgang Dr. Krämer
Karl Heinz Dr. Büchel
Jörg Dr. Stetter
Manfred Dr. Plempel
Ingo Dr. Haller
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Bayer AG
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Bayer AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/63—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/673—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by change of size of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C07C45/70—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form
    • C07C45/71—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form being hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/04—Saturated compounds containing keto groups bound to acyclic carbon atoms
    • C07C49/16—Saturated compounds containing keto groups bound to acyclic carbon atoms containing halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/04—Saturated compounds containing keto groups bound to acyclic carbon atoms
    • C07C49/16—Saturated compounds containing keto groups bound to acyclic carbon atoms containing halogen
    • C07C49/167—Saturated compounds containing keto groups bound to acyclic carbon atoms containing halogen containing only fluorine as halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/20—Unsaturated compounds containing keto groups bound to acyclic carbon atoms
    • C07C49/255—Unsaturated compounds containing keto groups bound to acyclic carbon atoms containing ether groups, groups, groups, or groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles

Definitions

  • the invention relates to antifungal agents which contain new fluorinated 1-imidazolyl-butane derivatives as the active ingredient, and to processes for the preparation of these agents.
  • the fluorinated 1-imidazolylbutane derivatives of the general formula which can be used according to the invention show better antifungal activity, in particular against candida, in vivo than the known chlorinated and brominated 1-imidazolylbutane derivatives, which are the most obvious compounds in chemical terms.
  • the substances which can be used according to the invention thus represent an enrichment of pharmacy.
  • Preferred fluorinated 1-imidazolylbutane derivatives are those in which Z is fluorine, chlorine, bromine, iodine, methyl, ethyl, nitro, cyano, methoxycarbonyl, ethoxycarbonyl, phenyl or chlorophenyl, the index n is 0, 1 or 2 stands and B and X have the meaning given in the definition of the invention.
  • sulfonic acid esters of the general formula VI are known (cf. J. Org. Chem., 35, 2391 [1970]).
  • the compounds not yet described can be prepared from the corresponding hydroxybutanones and sulfochlorides in the presence of bases by processes known from the literature (see, for example, Houben-Weyl, Methods of Org. Chemistry, Vol. IX, pp. 388 and 663, and the information given in the manufacturing examples).
  • All physiologically compatible acids are suitable for the preparation of acid addition salts of the compounds of the general formula 1.
  • These preferably include the hydrohalic acids, such as. B. the hydrochloric acid and hydrobromic acid, especially hydrochloric acid, also phosphoric acid, nitric acid, sulfuric acid, mono- and bifunctional carboxylic acids and hydroxycarboxylic acids, such as. B. acetic acid, maleic acid, succinic acid, fumaric acid, tartaric acid, citric acid, salicylic acid, sorbic acid, lactic acid and sulfonic acids, such as. B. p-toluenesulfonic acid and 1,5-naphthalenedisulfonic acid.
  • the hydrohalic acids such as. B. the hydrochloric acid and hydrobromic acid, especially hydrochloric acid, also phosphoric acid, nitric acid, sulfuric acid, mono- and bifunctional carboxylic acids and hydroxycarboxylic acids, such as. B. acetic acid, male
  • the salts of the compounds of the general formula I can be prepared in a simple manner by customary methods Salt formation methods, e.g. B. by dissolving a compound of general formula I in a suitable inert solvent and adding the acid, e.g. As hydrochloric acid can be obtained and in a known manner, for. B. by filtering, isolated and optionally cleaned by washing with an inert organic solvent.
  • Salt formation methods e.g. B. by dissolving a compound of general formula I in a suitable inert solvent and adding the acid, e.g. As hydrochloric acid can be obtained and in a known manner, for. B. by filtering, isolated and optionally cleaned by washing with an inert organic solvent.
  • Anions of the salts are those which are derived from physiological acids. These preferably include the hydrohalic acids, such as. B. the hydrochloric acid and hydrobromic acid, also phosphoric acid, nitric acid and sulfuric acid.
  • the metal salt complexes of the compounds of general formula 1 can be obtained in a simple manner by customary processes, for. B. by dissolving the metal salt in alcohol, e.g. B. ethanol, and adding to the compound of general formula I. You can metal salt complexes in a known manner, for. B. by filtering, isolating and optionally by recrystallization.
  • the active compounds of the agents of general formula I according to the invention have antimicrobial, in particular strong antifungal, effects. They have a very broad spectrum of antifungal effects, especially against dermatophytes and sprout fungi as well as biphasic fungi, e.g. B. against Candida species, such as Epidermophyton floccosum, Aspergillus species, such as Aspergillus niger and Aspergillus fumigatus, such as Trichophyton species, such as Trichophyton mentagrophytes, Microsporon species, such as Microsporon felineum and Penicillium species, such as Penicillium commune. The enumeration of these microorganisms does not in any way limit the number of germs which can be controlled, but is only of an explanatory nature.
  • Indications for use in human medicine include:
  • the invention includes pharmaceutical preparations which, in addition to non-toxic, inert pharmaceutically suitable excipients, contain one or more active compounds according to the invention and processes for the preparation of these preparations.
  • the invention also includes pharmaceutical preparations in dosage units.
  • the dosage units can e.g. B. 1, 2, or 4 single doses or 1 ⁇ 2 1/3 or 1/4 of an individual dose.
  • a single dose preferably contains the amount of active ingredient which is administered in one application and which usually corresponds to a whole, a half or a third or a quarter of a daily dose.
  • Non-toxic, inert pharmaceutically suitable excipients are to be understood as solid, semisolid or liquid diluents, fillers and formulation auxiliaries of all kinds.
  • Tablets, dragees, capsules, pills, granules, suppositories, solutions, suspensions and emulsions, pastes, ointments, gels, creams, lotions, powders and sprays may be mentioned as preferred pharmaceutical preparations.
  • Tablets, coated tablets, capsules, pills and granules can contain the active ingredient (s) in addition to the usual carriers, such as (a) fillers and extenders, e.g. B. starches, milk sugar, cane sugar, glucose, mannitol and silica, (b) binders, e.g. B. carboxymethyl cellulose, alginates, gelatin, polyvinyl pyrrolidone, (c) humectants, e.g. B. glycerin, (d) disintegrant, e.g. B. agar, calcium carbonate and sodium bicarbonate, (e) solution retarders, e.g. B. paraffin and (f) absorption accelerator, e.g. B.
  • fillers and extenders e.g. B. starches, milk sugar, cane sugar, glucose, mannitol and silica
  • binders e.g. B. carboxymethyl cellulose, alginates, gelatin, polyvinyl
  • quaternary ammonium compounds (g) wetting agents, e.g. B. cetyl alcohol, glycerol monostearate, (h) adsorbent, e.g. B. kaolin and bentonite and (i) lubricants, e.g. B. talc, calcium and magnesium stearate and solid polyethylene glycols or mixtures of the substances listed under (a) to (i).
  • wetting agents e.g. B. cetyl alcohol, glycerol monostearate
  • adsorbent e.g. B. kaolin and bentonite
  • lubricants e.g. B. talc, calcium and magnesium stearate and solid polyethylene glycols or mixtures of the substances listed under (a) to (i).
  • the tablets, dragees, capsules, pills and granules can be provided with the customary coatings and casings optionally containing opacifying agents and can also be composed such that they release the active ingredient (s) only or preferably in a certain part of the intestinal tract, optionally with a delay, where as Embedding compounds e.g. B. polymer substances and waxes can be used.
  • Embedding compounds e.g. B. polymer substances and waxes can be used.
  • the active ingredient (s) can optionally also be in microencapsulated form with one or more of the above-mentioned excipients.
  • Suppositories can contain the usual water-soluble or water-insoluble excipients in addition to the active ingredient or ingredients, e.g. B. polyethylene glycols, fats, e.g. B. cocoa fat and higher esters (z. B. C 14 alcohol with C 16 fatty acid) or mixtures of these substances.
  • B. polyethylene glycols e.g. B. polyethylene glycols
  • fats e.g. B. cocoa fat and higher esters (z. B. C 14 alcohol with C 16 fatty acid) or mixtures of these substances.
  • ointments, pastes, creams and gels can be the usual ones Contain carriers, e.g. B. animal and vegetable fats, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silica, talc and zinc oxide or mixtures of these substances.
  • Contain carriers e.g. B. animal and vegetable fats, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silica, talc and zinc oxide or mixtures of these substances.
  • Powder and sprays can contain the usual excipients in addition to the active ingredient (s), e.g. B. milk sugar, talc, silica, aluminum hydroxide, calcium silicate and polyamide powder or mixtures of these substances.
  • Sprays can also use the usual blowing agents, e.g. B. chlorofluorocarbons.
  • Solutions and emulsions can in addition to the active ingredient (s) the usual carriers such as solvents, solubilizers and emulsifiers, e.g. B. water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzylene benzate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, in particular cottonseed oil, peanut oil, corn oil, olive oil, castor oil and sesame oil, glycerin, glyceryl ether, fatty alcohol, fatty alcohol, fatty alcohol, fatty alcohol, fatty alcohol, fatty alcohol, fatty alcohol, fatty acid, fatty alcohol, fatty alcohol, fatty alcohol, fatty alcohol, fatty alcohol, fatty alcohol, fatty alcohol, fatty alcohol, fatty alcohol, fatty alcohol, fatty alcohol, fatty alcohol of sorbitan or mixtures of these substances.
  • solvents e.g. B
  • solutions and emulsions can also be in sterile and blood isotonic form.
  • suspensions can contain the usual carriers such as liquid diluents, e.g. B. water, ethyl alcohol, propylene glycol, suspending agents, e.g. B. ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum hydroxide, bentonite, agar and tragacanth or mixtures of these substances.
  • liquid diluents e.g. B. water, ethyl alcohol, propylene glycol
  • suspending agents e.g. B. ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum hydroxide, bentonite, agar and tragacanth or mixtures of these substances.
  • the formulation forms mentioned can also contain colorants, preservatives and odor and taste-improving additives, e.g. B. peppermint oil and eucalyptus oil and sweeteners, e.g. B. Sakharin included.
  • the therapeutically active compounds should be present in the pharmaceutical preparations listed above preferably in a concentration of about 0.1 to 99.5, preferably of about 0.5 to 95% by weight of the total mixture.
  • the pharmaceutical preparations listed above can also contain further pharmaceutical active substances.
  • the pharmaceutical preparations listed above are prepared in a conventional manner by known methods, e.g. B. by mixing the active ingredient (s) with the excipient (s).
  • the pharmaceutical preparations can be administered locally, orally, parenterally, intraperitoneally and / or rectally, preferably parenterally, in particular intravenously.
  • the active ingredient (s) according to the invention in total amounts of about 10 to about 300, preferably 50 to 200 mg / kg of body weight per 24 hours, optionally in the form of several individual doses to achieve the desired results.
  • the incubation temperature was 28 ° C; Incubation time was 24 hours for yeasts and 96 hours for dermatophytes and molds.
  • the agents according to the invention show good MIC values.
  • mice of the SPF-CF I type were infected intravenously with 1-2 x 10 6 logarithmically growing Candida cells which were suspended in physiological saline. One hour before and seven hours after the infection, the animals are treated orally with 50-100 mg / kg body weight of the preparations.
  • the closest known compounds show no action or only trace action, while the agents according to the invention show action ( ⁇ 60% survivors on the 6th day p. I.) To good action ( ⁇ 80% survivors on the 6th day p. I.).
  • Example 1 by reacting 3,3-bis-fluoromethyl-1- (4-chlorophenoxy) butan-2-one with bromine.
  • Example 1 by reacting 3,3-bisfluoromethyl-butan-2-one with bromine.
  • the aqueous phase is extracted with 1000 ml of methylene chloride; the solid is dissolved in the methylene chloride phase, the organic phase is dried over sodium sulfate, the solvent is distilled off in a water jet vacuum and the residue is suspended in 200 ml of ether. The residue is filtered off and washed with 100 ml of ether.

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Abstract

1. Antimycotic agent, characterised in that it contains at least one fluorinated 1-imidazolyl-butane derivative of the general formula I see diagramm : EP0019730,P13,F2 in which B represents the keto group or the CH(OH)-grouping, X represents hydrogen or fluorine, Z represents halogen, alkyl with 1 to 4 carbon atoms, nitro, cyano, alkoxycarbonyl with 1 to 4 carbon atoms in the alkyl part, or phenyl which is optionally substituted by halogen, and n represents 0, 1, 2 or 3, and/or physiologically acceptable acid addition salts and/or metal complexes thereof.

Description

Die Erfindung betrifft antimykotische Mittel, welche neue fluorierte 1-Imidazolyl-butan-Derivate als Wirkstoff enthalten sowie Verfahren zur Herstellung dieser Mittel.The invention relates to antifungal agents which contain new fluorinated 1-imidazolyl-butane derivatives as the active ingredient, and to processes for the preparation of these agents.

Es ist bereits bekanntgeworden, daß chlorierte und bromierte 1-Imidazolyl-butan-Derivate gute antimykotische Eigenschaften aufweisen (vgl. DE-A-2 632 601). Die Wirksamkeit dieser Verbindungen ist jedoch, insbesondere in-vivo gegen Candida, nicht immer ganz befriedigend.It has already become known that chlorinated and brominated 1-imidazolyl-butane derivatives have good antifungal properties (cf. DE-A-2 632 601). However, the effectiveness of these compounds, in particular against Candida in vivo, is not always entirely satisfactory.

Es wurde gefunden, daß die neuen fluorierten 1-Imidazolyl-butan-Derivate der allgemeinen Formel

Figure imgb0001
in welcher

  • B für die Ketogruppe oder die CH(OH)-Gruppierung steht,
  • X für Wasserstoff oder Fluor steht,
  • Z für Halogen, Alkyl mit 1 -4 C-Atomen, Nitro, Cyano, Alkoxycarbonyl mit 1 -4 C-Atomen im Alkylteil sowie für gegebenenfalls durch Halogen substituiertes Phenyl steht und
  • n für 0, 1, oder 3 steht,

und deren physiologisch verträglichen Säureadditions-Salze und Metallsalz-Komplexe gute
antimikrobielle, insbesondere antimykotische Eigenschaften aufweisen.It has been found that the new fluorinated 1-imidazolyl-butane derivatives of the general formula
Figure imgb0001
 in which
  • B represents the keto group or the CH (OH) grouping,
  • X represents hydrogen or fluorine,
  • Z represents halogen, alkyl having 1 -4 C atoms, nitro, cyano, alkoxycarbonyl having 1 -4 C atoms in the alkyl part and also phenyl which is optionally substituted by halogen and
  • n represents 0, 1 or 3,

and their physiologically acceptable acid addition salts and metal salt complexes are good
have antimicrobial, in particular antifungal properties.

Diejenigen Verbindungen der allgemeinen Formel in welchen B für die CH(OH)-Gruppierung steht, besitzen zwei asymmetrische Kohlenstoffatome; sie können deshalb in den beiden geometrischen Isomeren (threo- und erythro-Form) vorliegen, die in unterschiedlichen Mengenverhältnissen anfallen können. In beiden Fällen liegen sie als optische Isomeren vor. Sämtliche Isomeren werden erfindungsgemäß beansprucht.Those compounds of the general formula in which B represents the CH (OH) grouping have two asymmetric carbon atoms; they can therefore exist in the two geometric isomers (threo and erythro form), which can be obtained in different proportions. In both cases they exist as optical isomers. All isomers are claimed according to the invention.

Überraschenderweise zeigen die erfindungsgemäß verwendbaren fluorierten 1-Imidazolyl-butan-Derivate der allgemeinen Formel eine bessere antimykotische Wirksamkeit, insbesondere in vivo gegen Candida, als die bekannten chlorierten und bromierten 1-Imidazolyl-butan-Derivate, die chemisch die naheliegendsten Verbindungen sind. Die erfindungsgemäß verwendbaren Stoffe stellen somit eine Bereicherung der Pharmazie dar.Surprisingly, the fluorinated 1-imidazolylbutane derivatives of the general formula which can be used according to the invention show better antifungal activity, in particular against candida, in vivo than the known chlorinated and brominated 1-imidazolylbutane derivatives, which are the most obvious compounds in chemical terms. The substances which can be used according to the invention thus represent an enrichment of pharmacy.

Bevorzugt sind diejenigen fluorierten 1-Imidazolyl-butan-Derivate, in denen Z für Fluor, Chlor, Brom, Jod, Methyl, Ethyl, Nitro, Cyano, Methoxycarbonyl, Ethoxycarbonyl, Phenyl oder Chlorphenyl steht, der Index n für 0, 1 oder 2 steht und B sowie X die in der Erfindungsdefinition angegebene Bedeutung haben.Preferred fluorinated 1-imidazolylbutane derivatives are those in which Z is fluorine, chlorine, bromine, iodine, methyl, ethyl, nitro, cyano, methoxycarbonyl, ethoxycarbonyl, phenyl or chlorophenyl, the index n is 0, 1 or 2 stands and B and X have the meaning given in the definition of the invention.

Im einzelnen seien außer den bei den Herstellungsbeispielen genannten Verbindungen die folgenden Verbindungen der allgemeinen Formel genannt:

Figure imgb0002
Figure imgb0003
 In addition to the compounds mentioned in the preparation examples, the following compounds of the general formula may be mentioned individually:
Figure imgb0002
Figure imgb0003

Fortsetzungcontinuation

Figure imgb0004
Figure imgb0004

Die erfindungsgemäß zu verwendenden Wirkstoffe, deren Säureadditions-Saize und Metallsalz- Komplexe sind nocht nicht bekannt. Sie können jedoch gemäß einem eigenen Vorschlag hergestellt werden, indem man Halogenetherketone der allgemeinen Formel II

Figure imgb0005
in welcher

  • X, Z und n die oben angegebene Bedeutung haben und
  • Hal für Halogen, vorzugsweise Chlor oder Brom steht,

mit Imidazol in Gegenwart eines Säurebindemittels, wie beispielsweise Natriumcarbonat oder ein Überschuß an lmidazol, und gegebenenfalls in Gegenwart eines inerten organischen Lösungsmittels, wie beispielsweise Aceton oder Acetonitril, bei Temperaturen zwischen 60 und 120°C umsetzt und gegebenenfalls noch die erhaltenen Keto-Derivate nach bekannten Methoden reduziert, wie z. B. durch Umsetzung mit komplexen Hydriden, wie insbesondere Natriumborhydrid, gegebenenfalls in Gegenwart eines polaren organischen Lösungsmittels, wie beispielsweise Alkohole, bei Temperaturen zwischen 0 und 30° C; oder durch Umsetzung mit Aluminiumisopropylat in Gegenwart eines inerten organischen Lösungsmittels, wie beispielsweise Isopropanol, bei Temperaturen zwischen 20 und 120°C. Die Aufarbeitung erfolgt in üblicher Weise; gegebenenfalls wird das Salz oder ein Metallkomplex hergestellt. In manchen Fällen erweist es sich als vorteilhaft, die Verbindungen der allgemeinen Formel über ihre Salze in reiner Form zu erhalten.The active ingredients to be used according to the invention, their acid addition salts and metal salt complexes are not yet known. However, they can be prepared according to a separate proposal by halogen ether ketones of the general formula II
Figure imgb0005
 in which
  • X, Z and n have the meaning given above and
  • Hal represents halogen, preferably chlorine or bromine,

with imidazole in the presence of an acid binder, such as sodium carbonate or an excess of imidazole, and optionally in the presence of an inert organic solvent, such as acetone or acetonitrile, at temperatures between 60 and 120 ° C and optionally still the keto derivatives obtained according to known Reduced methods such. B. by reaction with complex hydrides, such as in particular sodium borohydride, optionally in the presence of a polar organic solvent, such as alcohols, at temperatures between 0 and 30 ° C; or by reaction with aluminum isopropylate in the presence of an inert organic solvent, such as isopropanol, at temperatures between 20 and 120 ° C. The processing takes place in the usual way; optionally the salt or a metal complex is produced. In some cases it proves advantageous to obtain the compounds of the general formula in pure form via their salts.

Die Halogenetherketone der allgemeinen Formel II sind noch nicht bekannt. Sie können jedoch nach bekannten Verfahren (vgl. z. B. DE-A-2 632 603) erhalten werden, indem man z. B. bekannte Phenole der allgemeinen Formel 111

Figure imgb0006
in welcher

  • Z und n die oben angegebene Bedeutung haben,
    mit einem Halogenketon der allgemeinen Formel IV
    Figure imgb0007
    in welcher
  • X die oben angegebene Bedeutung hat und
  • Hal' für Chlor oder Brom steht,

umsetzt. Das noch verbliebene aktive Wasserstoffatom wird anschließend in üblicher Weise gegen Halogen ausgetauscht (vgl. auch die Herstellungsbeispiele).The halogen ether ketones of the general formula II are not yet known. However, they can be obtained by known processes (cf., for example, DE-A-2 632 603) by, for. B. known phenols of the general formula III
Figure imgb0006
 in which
  • Z and n have the meaning given above,
    with a halogen ketone of the general formula IV
    Figure imgb0007
     in which
  • X has the meaning given above and
  • Hal 'represents chlorine or bromine,

implements. The remaining active hydrogen atom is then exchanged for halogen in the usual way (see also the preparation examples).

Die Halogenketone der allgemeinen Formel IV sind ebenfalls noch nicht bekannt. Sie können jedoch auf allgemein übliche und bekannte Weise erhalten werden, indem man Fluorderivate des 3,3-Dimethyl-butan-2-ons der allgemeinen Formel V

Figure imgb0008
in welcher -

  • X die oben angegebene Bedeutung hat,
    mit Chlor oder Brom in Gegenwart eines inerten organischen Lösungsmittels, wie beispielsweise Ether oder chlorierte Kohlenwasserstoffe, bei Raumtemperatur versetzt (vgl. auch die Herstellungsbeispiele), oder mit üblichen Chlorierungsmitteln, wie beispielsweise Sulfurylchlorid bei 20 bis 60°C umsetzt. Die Fluorderivate des 3,3-Dimethyl-butan-2-ons der allgemeinen Formel V sind aus der DE-A-2 843 767 bekannt. Man erhält sie, wenn man Sulfonsäureester der allgemeinen Formel Vi
    Figure imgb0009
    in welcher
  • R für Alkyl mit 1 bis 4 Kohlenstoffatomen, insbesondere Methyl, oder Aryl mit 6 bis 12 Kohlenstoffatomen, insbesondere Phenyl oder Tolyl, steht und
  • Y für Wasserstoff oder die Gruppe ―O―SO2―R steht,

mit Metallfluoriden, wie beispielsweise Natrium- und Kaliumfluorid, in Gegenwart eines polaren organischen Lösungsmittels, wie beispielsweise Di-, Tri- oder Tetraethylenglykol, bei Temperaturen zwischen 80 und 250° C umsetzt (vgl. auch die Herstellungsbeispiele).The halogen ketones of the general formula IV are also not yet known. However, they can be obtained in a generally customary and known manner by using fluorine derivatives of 3,3-dimethyl-butan-2-one of the general formula V
Figure imgb0008
 in which -
  • X has the meaning given above,
    with chlorine or bromine in the presence of an inert organic solvent, such as, for example, ether or chlorinated hydrocarbons, at room temperature (see also the preparation examples), or with conventional chlorinating agents, such as, for example, sulfuryl chloride at 20 to 60 ° C. The fluorine derivatives of 3,3-dimethyl-butan-2-one of the general formula V are known from DE-A-2 843 767. They are obtained if sulfonic acid esters of the general formula Vi
    Figure imgb0009
     in which
  • R represents alkyl having 1 to 4 carbon atoms, in particular methyl, or aryl having 6 to 12 carbon atoms, in particular phenyl or tolyl, and
  • Y represents hydrogen or the group ―O ― SO 2 ―R,

with metal fluorides, such as sodium and potassium fluoride, in the presence of a polar organic solvent, such as di-, tri- or tetraethylene glycol, at temperatures between 80 and 250 ° C (see also the preparation examples).

Die Sulfonsäureester der allgemeinen Formel VI sind teilweise bekannt (vgl. J. Org. Chem., 35, 2391 [1970]). Die noch nicht beschriebenen Verbindungen können nach literaturbekannten Verfahren aus den entsprechenden Hydroxybutanonen und Sulfochloriden in Gegenwart von Basen hergestellt werden (siehe z. B. Houben-Weyl, Methoden der Org. Chemie, Bd. IX, S. 388 und 663, sowie die Angaben bei den Herstellungsbeispielen).Some of the sulfonic acid esters of the general formula VI are known (cf. J. Org. Chem., 35, 2391 [1970]). The compounds not yet described can be prepared from the corresponding hydroxybutanones and sulfochlorides in the presence of bases by processes known from the literature (see, for example, Houben-Weyl, Methods of Org. Chemistry, Vol. IX, pp. 388 and 663, and the information given in the manufacturing examples).

Zur Herstellung von Säureadditionssalzen der Verbindungen der allgemeinen Formel 1 kommen alle physiologisch verträglichen Säuren in Frage. Hierzu gehören vorzugsweise die Halogenwasserstoffsäuren, wie z. B. die Chlorwasserstoffsäure und die Bromwasserstoffsäure, insbesondere die Chlorwasserstoffsäure, ferner Phosphorsäure, Salpetersäure, Schwefelsäure, mono- und bifunktionelle Carbonsäuren und Hydroxycarbonsäuren, wie z. B. Essigsäure, Maleinsäure, Bernsteinsäure, Fumarsäure, Weinsäure, Zitronensäure, Salizylsäure, Sorbinsäure, Milchsäure sowie Sulfonsäuren, wie z. B. p-Toluolsulfonsäure und 1,5-Naphthalindisulfonsäure.All physiologically compatible acids are suitable for the preparation of acid addition salts of the compounds of the general formula 1. These preferably include the hydrohalic acids, such as. B. the hydrochloric acid and hydrobromic acid, especially hydrochloric acid, also phosphoric acid, nitric acid, sulfuric acid, mono- and bifunctional carboxylic acids and hydroxycarboxylic acids, such as. B. acetic acid, maleic acid, succinic acid, fumaric acid, tartaric acid, citric acid, salicylic acid, sorbic acid, lactic acid and sulfonic acids, such as. B. p-toluenesulfonic acid and 1,5-naphthalenedisulfonic acid.

Die Salze der Verbindungen der allgemeinen Formel I können in einfacher Weise nach üblichen Salzbildungsmethoden, z. B. durch Lösen einer Verbindung der allgemeinen Formel I in einem geeigneten inerten Lösungsmittel und Hinzufügen der Säure, z. B. Chlorwasserstoffsäure, erhalten werden und in bekannter Weise, z. B. durch Abfiltrieren, isoliert und gegebenenfalls durch Waschen mit einem inerten organischen Lösungsmittel gereinigt werden.The salts of the compounds of the general formula I can be prepared in a simple manner by customary methods Salt formation methods, e.g. B. by dissolving a compound of general formula I in a suitable inert solvent and adding the acid, e.g. As hydrochloric acid can be obtained and in a known manner, for. B. by filtering, isolated and optionally cleaned by washing with an inert organic solvent.

Zur Herstellung von Metallsalz-Komplexen der Verbindungen der allgemeinen Formel I kommen vorzugsweise Salze von Metallen der II. bis IV. Haupt- und der I. und II. sowie IV. bis VIII. Nebengruppe in Frage, wobei Kupfer, Zink, Mangan, Magnesium, Zinn, Eisen und NiGkel beispielhaft genant seien. Als Anionen der Salze kommen solche in Betracht, die sich von physiologischen Säuren ableiten. Hierzu gehören vorzugsweise die Halogenwasserstoffsäuren, wie z. B. die Chlorwasserstoffsäure und die Bromwasserstoffsäure, ferner Phosphorsäure, Salpetersäure und Schwefelsäure.For the preparation of metal salt complexes of the compounds of the general formula I, preference is given to salts of metals of the II. To IV. Main group and of I. and II. And IV. To VIII. Subgroup, copper, zinc, manganese, magnesium , tin, iron and Ni G are genant kel example. Anions of the salts are those which are derived from physiological acids. These preferably include the hydrohalic acids, such as. B. the hydrochloric acid and hydrobromic acid, also phosphoric acid, nitric acid and sulfuric acid.

Die Metallsalzkomplexe der Verbindungen der allgemeinen Formel 1 können in einfacher Weise nach üblichen Verfahren erhalten werden, so z. B. durch Lösen des Metallsalzes in Alkohol, z. B. Äthanol, und Hinzufügen zur Verbindung der allgemeinen Formel I. Man kann Metallsalzkomplexe in bekannter Weise, z. B. durch Abfiltrieren, Isolieren und gegebenenfalls durch Umkristallisieren reinigen.The metal salt complexes of the compounds of general formula 1 can be obtained in a simple manner by customary processes, for. B. by dissolving the metal salt in alcohol, e.g. B. ethanol, and adding to the compound of general formula I. You can metal salt complexes in a known manner, for. B. by filtering, isolating and optionally by recrystallization.

Die Wirkstoffe der erfindungsgemäßen Mittel der allgemeinen Formel I, ihre Säureadditions-Salze und Metallsalz-Komplexe weisen antimikrobielle, insbesondere starke antimykotische Wirkungen auf. Sie besitzen ein sehr breites antimykotisches Wirkungsspektrum, insbesondere gegen Dermatophyten und Sproßpilze sowie biphasische Pilze, z. B. gegen Candida-Arten, wie Epidermophyton floccosum, Aspergillus-Arten, wie Aspergillus niger und Aspergillus fumigatus, wie Trichophyton-Arten, wie Trichophyton mentagrophytes, Microsporon-Arten, wie Microsporon felineum sowie Penicillium-Arten, wie Penicillium commune. Die Aufzählung dieser Mikroorganismen stellt keinesfalls eine Beschränkung der bekämpfbaren Keime dar, sondern hat nur erläuternden Charakter.The active compounds of the agents of general formula I according to the invention, their acid addition salts and metal salt complexes have antimicrobial, in particular strong antifungal, effects. They have a very broad spectrum of antifungal effects, especially against dermatophytes and sprout fungi as well as biphasic fungi, e.g. B. against Candida species, such as Epidermophyton floccosum, Aspergillus species, such as Aspergillus niger and Aspergillus fumigatus, such as Trichophyton species, such as Trichophyton mentagrophytes, Microsporon species, such as Microsporon felineum and Penicillium species, such as Penicillium commune. The enumeration of these microorganisms does not in any way limit the number of germs which can be controlled, but is only of an explanatory nature.

Als Indikationsgebiete in der Humanmedizin können beispielsweise genannt werden:Indications for use in human medicine include:

Dermatomykosen und Systemmykosen durch Trichophyton mentagrophytes und andere Trichophytonarten, Mikrosporonarten, Epidermophyton floccosum, Sproßpilze und biphasische Pilze sowie Schimmelpilze hervorgerufen.Dermatomycoses and systemic mycoses caused by Trichophyton mentagrophytes and other Trichophyton species, microsporon species, Epidermophyton floccosum, shoots and biphasic fungi as well as molds.

Als Indikationsgebiet in der Tiermedizin können beispielsweise aufgeführt werden:

  • Alle Dermatomykosen und Systemmykosen, insbesondere solche, die durch die obengenannten Erreger hervorgerufen werden.
For example, the following can be listed as an indication area in veterinary medicine:
  • All dermatomycoses and systemic mycoses, especially those caused by the pathogens mentioned above.

Zur Erfindung gehören pharmazeutische Zubereitungen, die neben nicht toxischen, inerten pharmazeutisch geeigneten Trägerstoffen einen oder mehrere erfindungsgemäße Wirkstoffe enthalten sowie Verfahren zur Herstellung dieser Zubereitungen.The invention includes pharmaceutical preparations which, in addition to non-toxic, inert pharmaceutically suitable excipients, contain one or more active compounds according to the invention and processes for the preparation of these preparations.

Zur Erfindung gehören auch pharmazeutische Zubereitungen in Dosierungseinheiten. Dies bedeutet, daß die Zubereitungen in Form einzelner Teile, z. B. Tabletten, Dragees, Kapseln, Pillen, Suppositorien und Ampullen vorlieden, deren Wirkstoffgehalt einem Bruchteil oder einem Vielfachen einer Einzeldosis entsprechen. Die Dosierungseinheiten können z. B. 1, 2, oder 4 Einzeldosen oder ½, 1/3 oder 1/4 einer Einzeldosis enthalten. Eine Einzeldosis enthält vorzugsweise die Menge Wirkstoff, die bei einer Applikation verabreicht wird und die gewöhnlich einer ganzen, einer halben oder einem Drittel oder einem Viertel einer Tagesdosis entspricht.The invention also includes pharmaceutical preparations in dosage units. This means that the preparations in the form of individual parts, for. B. tablets, dragees, capsules, pills, suppositories and ampoules, the active ingredient content of which corresponds to a fraction or a multiple of a single dose. The dosage units can e.g. B. 1, 2, or 4 single doses or ½ 1/3 or 1/4 of an individual dose. A single dose preferably contains the amount of active ingredient which is administered in one application and which usually corresponds to a whole, a half or a third or a quarter of a daily dose.

Unter nicht toxischen, inerten pharmazeutisch geeigneten Trägerstoffen sind feste, halbfeste oder flüssige Verdünnungsmittel, Füllstoffe und Formulierungshilfsmittel jeder Art zu verstehen.Non-toxic, inert pharmaceutically suitable excipients are to be understood as solid, semisolid or liquid diluents, fillers and formulation auxiliaries of all kinds.

Als bevorzugte pharmazeutische Zubereitungen seien Tabletten, Dragees, Kapseln, Pillen, Granulate, Suppositorien, Lösungen, Suspensionen und Emulsionen, Pasten, Salben, Gele, Cremes, Lotions, Puder und Sprays genannt.Tablets, dragees, capsules, pills, granules, suppositories, solutions, suspensions and emulsions, pastes, ointments, gels, creams, lotions, powders and sprays may be mentioned as preferred pharmaceutical preparations.

Tabletten, Dragees, Kapseln, Pillen und Granulate können den oder die Wirkstoffe neben den üblichen Trägerstoffen enthalten, wie (a) Füll- und Streckmittel, z. B. Stärken, Milchzucker, Rohrzucker, Glukose, Mannit und Kieselsäure, (b) Bindemittel, z. B. Carboxymethylcellulose, Alginate, Gelatine, Polyvinylpyrrolidon, (c) Feuchthaltemittel, z. B. Glycerin, (d) Sprengmittel, z. B. Agar-Agar, Calciumcarbonat und Natriumbicarbonat, (e) Lösungsverzögerer, z. B. Paraffin und (f) Resorptionsbeschleuniger, z. B. quartenäre Ammoniumverbindungen, (g) Netzmittel, z. B. Cetylalkohol, Glycerinmonostearat, (h) Adsorptionsmittel, z. B. Kaolin und Bentonit und (i) Gleitmittel, z. B. Talkum, Calcium-und Magnesiumstearat und feste Polyäthylenglykole oder Gemische der unter (a) bis (i) aufgeführten Stoffe.Tablets, coated tablets, capsules, pills and granules can contain the active ingredient (s) in addition to the usual carriers, such as (a) fillers and extenders, e.g. B. starches, milk sugar, cane sugar, glucose, mannitol and silica, (b) binders, e.g. B. carboxymethyl cellulose, alginates, gelatin, polyvinyl pyrrolidone, (c) humectants, e.g. B. glycerin, (d) disintegrant, e.g. B. agar, calcium carbonate and sodium bicarbonate, (e) solution retarders, e.g. B. paraffin and (f) absorption accelerator, e.g. B. quaternary ammonium compounds, (g) wetting agents, e.g. B. cetyl alcohol, glycerol monostearate, (h) adsorbent, e.g. B. kaolin and bentonite and (i) lubricants, e.g. B. talc, calcium and magnesium stearate and solid polyethylene glycols or mixtures of the substances listed under (a) to (i).

Den Tabletten, Dragees, Kapseln, Pillen und Granulate können mit den üblichen gegebenenfalls Opakisierungsmittel enthaltenden Überzügen und Hüllen versehen sein und auch so zusammengesetzt sein, daß sie den oder die Wirkstoffe nur oder bevorzugt in einem bestimmten Teil des Intestinaltraktes, gegebenenfalls verzögert abgeben, wobei als Einbettungsmassen z. B. Polymersubstanzen und Wachse verwendet werden können.The tablets, dragees, capsules, pills and granules can be provided with the customary coatings and casings optionally containing opacifying agents and can also be composed such that they release the active ingredient (s) only or preferably in a certain part of the intestinal tract, optionally with a delay, where as Embedding compounds e.g. B. polymer substances and waxes can be used.

Der oder die Wirkstoffe können gegebenenfalls mit einem oder mehreren der oben angegebenen Trägerstoffen auch in mikroverkapselter Form vorliegen.The active ingredient (s) can optionally also be in microencapsulated form with one or more of the above-mentioned excipients.

Suppositorien können neben dem oder den Wirkstoffen die üblichen wasserlöslichen oder wasserunlöslichen Trägerstoffe enthalten, z. B. Polyäthylenglykole, Fette, z. B. Kakaofett und höhere Ester (z. B. C14-Alkohol mit C16-Fettsäure) oder Gemische dieser Stoffe.Suppositories can contain the usual water-soluble or water-insoluble excipients in addition to the active ingredient or ingredients, e.g. B. polyethylene glycols, fats, e.g. B. cocoa fat and higher esters (z. B. C 14 alcohol with C 16 fatty acid) or mixtures of these substances.

Salben, Pasten, Cremes und Gele können neben dem oder den Wirkstoffen die üblichen Trägerstoffe enthalten, z. B. tierische und pflanzliche Fette, Wachse, Paraffine, Stärke, Tragant, Cellulosederivate, Polyäthylenglykole, Silicone, Bentonite, Kieselsäure, Talkum und Zinkoxid oder Gemische dieser Stoffe.In addition to the active ingredient or ingredients, ointments, pastes, creams and gels can be the usual ones Contain carriers, e.g. B. animal and vegetable fats, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silica, talc and zinc oxide or mixtures of these substances.

Puder und Sprays können neben dem oder den Wirkstoffen die üblichen Trägerstoffe enthalten, z. B. Milchzucker, Talkum, Kieselsäure, Aluminiumhydroxid, Calciumsilikat und Polyamidpulver oder Gemische dieser Stoffe. Sprays können zusätzlich die üblichen Treibmittel, z. B. Chlorfluorkohlenwasserstoffe, enthalten.Powder and sprays can contain the usual excipients in addition to the active ingredient (s), e.g. B. milk sugar, talc, silica, aluminum hydroxide, calcium silicate and polyamide powder or mixtures of these substances. Sprays can also use the usual blowing agents, e.g. B. chlorofluorocarbons.

Lösungen und Emulsionen können neben dem oder den Wirkstoffen die üblichen Trägerstoffe wie Lösungsmittel, Lösungsvermittler und Emulgatoren, z. B. Wasser, Äthylalkohol, Isopropylalkohol, Äthylcarbonat, Äthylacetat, Benzylalkohol, Benzylenzoat, Propylenglykol, 1,3-Butylenglykol, Dimethylformamid, Öle, insbesondere Baumwollsaatöl, Erdnußöl, Maiskeimöl, Olivenöl, Ricinusöl und Sesamöl, Glycerin, Glycerinformal, Tetrahydrofurfurylalkohol, Polyäthylenglykole und Fettsäureester des Sorbitans oder Gemische dieser Stoffe enthalten.Solutions and emulsions can in addition to the active ingredient (s) the usual carriers such as solvents, solubilizers and emulsifiers, e.g. B. water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzylene benzate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, in particular cottonseed oil, peanut oil, corn oil, olive oil, castor oil and sesame oil, glycerin, glyceryl ether, fatty alcohol, fatty alcohol, fatty alcohol, fatty alcohol, fatty alcohol, fatty alcohol, fatty acid, fatty alcohol, fatty alcohol, fatty alcohol, fatty alcohol, fatty alcohol, fatty alcohol, fatty alcohol, fatty alcohol, fatty alcohol, fatty alcohol of sorbitan or mixtures of these substances.

Zur parenteralen Applikation können die Lösungen und Emulsionen auch in steriler und blutisotonischer Form vorliegen.For parenteral administration, the solutions and emulsions can also be in sterile and blood isotonic form.

Suspensionen können neben dem oder den Wirkstoffen die üblichen Trägerstoffe wie flüssige Verdünnungsmittel, z. B. Wasser, Äthylalkohol, Propylenglykol, Suspendiermittel, z. B. äthoxylierte Isostearylalkohole, Polyoxyäthylensorbit- und Sorbitanester, mikrokristalline Cellulose, Aluminiummetahydroxid, Bentonit, Agar-Agar und Tragant oder Gemische dieser Stoffe enthalten.In addition to the active ingredient (s), suspensions can contain the usual carriers such as liquid diluents, e.g. B. water, ethyl alcohol, propylene glycol, suspending agents, e.g. B. ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum hydroxide, bentonite, agar and tragacanth or mixtures of these substances.

Die genannten Formulierungsformen können auch Färbemittel, Konservierungsstoffe sowie geruchs- und geschmackverbessernde Zusätze, z. B. Pfefferminzöl und Eukalyptusöl und Süßmittel, z. B. Sacharin, enthalten.The formulation forms mentioned can also contain colorants, preservatives and odor and taste-improving additives, e.g. B. peppermint oil and eucalyptus oil and sweeteners, e.g. B. Sakharin included.

Die therapeutisch wirksamen Verbindungen sollen in den oben aufgeführten pharmazeutischen Zubereitungen vorzugsweise in einer Konzentration von etwa 0,1 bis 99,5, vorzugsweise von etwa 0,5 bis 95 Gew.-% der Gesamtmischung vorhanden sein.The therapeutically active compounds should be present in the pharmaceutical preparations listed above preferably in a concentration of about 0.1 to 99.5, preferably of about 0.5 to 95% by weight of the total mixture.

Die oben aufgeführten pharmazeutischen Zubereitungen können außer den erfindungsgemäßen Wirkstoffen auch weitere pharmazeutische Wirkstoffe enthalten.In addition to the active substances according to the invention, the pharmaceutical preparations listed above can also contain further pharmaceutical active substances.

Die Herstellung der oben aufgeführten pharmazeutischen Zubereitungen erfolgt in üblicher Weise nach bekannten Methoden, z. B. durch Mischen des oder der Wirkstoffe mit dem oder den Trägerstoffen.The pharmaceutical preparations listed above are prepared in a conventional manner by known methods, e.g. B. by mixing the active ingredient (s) with the excipient (s).

Die pharmazeutischen Zubereitungen können lokal, oral, parenteral, intraperitoneal und/oder rectal, vorzugsweise parenteral, insbesondere intravenös appliziert werden.The pharmaceutical preparations can be administered locally, orally, parenterally, intraperitoneally and / or rectally, preferably parenterally, in particular intravenously.

Im allgemeinen hat es sich sowohl in der Human- als auch in der Veterinärmedizin als vorteilhaft erwiesen, den oder die erfindungsgemäßen Wirkstoffe in Gesamtmengen von etwa 10 bis etwa 300, vorzugsweise 50 bis 200 mg/kg Körpergewicht je 24 Stunden, gegebenenfalls in Form mehrerer Einzelgaben zur Erzielung der gewünschten Ergebnisse zu verabreichen.In general, it has proven to be advantageous in both human and veterinary medicine to use the active ingredient (s) according to the invention in total amounts of about 10 to about 300, preferably 50 to 200 mg / kg of body weight per 24 hours, optionally in the form of several individual doses to achieve the desired results.

Es kann jedoch erforderlich sein, von den genannten Dosierungen abzuweichen, und zwar in Abhängigkeit von der Art und dem Körpergewicht des zu behandelnden Objekts, der Art und der Schwere der Erkrankung, der Art der Zubereitung und der Applikation des Arzneimittels sowie dem Zeitraum bzw. Intervall, innerhalb welchem die Verabreichung erfolgt. So kann es in einigen Fällen ausreichend sein, mit weniger als der obengenannten Menge Wirkstoff auszukommen, wähernd in anderen Fällen die oben angeführte Wirkstoffmenge überschritten werden muß. Die Festlegung der jeweils erforderlichen optimalen Dosierung und Applikationsart der Wirkstoffe kann durch jeden Fachmann aufgrund seines Fachwissens leicht erfolgend.However, it may be necessary to deviate from the doses mentioned, depending on the type and body weight of the object to be treated, the type and severity of the disease, the type of preparation and administration of the drug, and the period or interval within which the administration takes place. In some cases it may be sufficient to make do with less than the above-mentioned amount of active ingredient, whereas in other cases the above-mentioned amount of active ingredient must be exceeded. The determination of the respectively required optimal dosage and type of application of the active substances can easily be done by any expert on the basis of his specialist knowledge.

Beispiel AExample A Antimykotische in-vitro-WirksamkeitIn vitro antifungal activity VersuchsbeschreibungExperiment description

Die in-vitro-Prüfung wurde im Reihenverdünnungstest mit Keiminokula von durchschnittlich 5 x 10 Keimen/ml Substrat durchgeführt. Als Nährmedium dienten

  • a) für Dermatophyten und Schimmelpilze: Sabourand's milieu d'epresive,
  • b) für Hefen: Isotonic Sensitest-Broth von Oxid.
The in-vitro test was carried out in a serial dilution test with germinocula with an average of 5 x 10 germs / ml of substrate. Served as a nutrient medium
  • a) for dermatophytes and molds: Sabourand's milieu d'epresive,
  • b) for yeasts: Isotonic Sensitest-Broth by Oxid.

Die Bebrütungstemperatur betrug 28°C; Bebrütungszeit war 24 Stunden bei Hefen und 96 Stunden bei Dermatophyten und Schimmelpilzen.The incubation temperature was 28 ° C; Incubation time was 24 hours for yeasts and 96 hours for dermatophytes and molds.

In dieser Versuchsanordnung zeigen die erfindungsgemäßen Mittel gute MHK-Werte.In this experimental arrangement, the agents according to the invention show good MIC values.

Beispiel BExample B Antimikrobielle in-vivo-Wirksamkeit {oral} bei Mäuse-CandidoseIn vivo antimicrobial efficacy in oral candidiasis VersuchsbeschreibungExperiment description

Mäuse vom Typ SPF-CFI wurden intravenös mit 1-2 x 106 logarithmisch wachsenden Candida-Zellen, die in physilogischer Kochsalzlösung suspendiert waren, infiziert. Eine Stunde vor und sieben Stunden nach der Infektion werden die Tiere mit jeweils 50-100 mg/kg Körpergewicht der Präparate oral behandelt.Mice of the SPF-CF I type were infected intravenously with 1-2 x 10 6 logarithmically growing Candida cells which were suspended in physiological saline. One hour before and seven hours after the infection, the animals are treated orally with 50-100 mg / kg body weight of the preparations.

ErgebnisResult

Unbehandelte Tiere starben 3 bis 6 Tage post infectionem. Die Überlebensrate am 6. Tag post infectionem betrug bei unbehandelten Kontrolltieren etwa 5%. Die nächstliegenden bekannten Verbindungen zeigen keine Wirkung oder nur Spurenwirkung, während die erfindungsgemäßen Mittel Wirkung (≥60% Überlebende am 6. Tage p. i.) bis gute Wirkung (≥80% Überlebende am 6. Tage p. i.) zeigen.Untreated animals died 3 to 6 days after infection. The survival rate on the 6th day after infection was approximately 5% in untreated control animals. The closest known compounds show no action or only trace action, while the agents according to the invention show action (≥60% survivors on the 6th day p. I.) To good action (≥80% survivors on the 6th day p. I.).

Beispiel 1example 1

Figure imgb0010
Figure imgb0010

157,5 g (0,44 Mol) 1-Brom-1-(2,4-dichlorphenoxy)-3,3-dimethyl-4-fluor-2-butanon werden in 500 rnl Acetonitril gelöst und zu einer Lösung von 109 g (1,6 Mol) Imidazol in 600 ml Acetonitril getropft. Man erhitzt 10 Stunden unter Rückfluß. Danach wird das Lösungsmittel im Wasserstrahlvakuum abdestilliert, der Rückstand in 1000 ml Methylenchlorid aufgenommen und dreimal mit je 500 ml Wasser gewaschen. Die organische Phase wird über Natriumsulfat getrocknet, filtriert und im Wasserstrahlvakuum durch Abdestillieren des Lösungsmittels eingeengt. Der Rückstand wird in 500 ml Ethanol gelöst, mit je 40 ml konzentrierter Salzsäure versetzt und das Lösungsmittel im Wasserstrahlvakuum abdestilliert. Der Rückstand wird mit 500 ml Ether verrührt, wobei es zur Kristallisation kommt. Man erhält 66 g (39,3% der Theorie) 1-(2,4-Dichlorphenoxy)-3,3-dimethyl-4-fluor-1-(imidazol-1-yl)-2-butanon-hydrochlorid vom Schmelzpunkt 91-110°C.157.5 g (0.44 mol) of 1-bromo-1- (2,4-dichlorophenoxy) -3,3-dimethyl-4-fluoro-2-butanone are dissolved in 500 ml of acetonitrile and to a solution of 109 g (1.6 mol) imidazole added dropwise in 600 ml of acetonitrile. The mixture is heated under reflux for 10 hours. The solvent is then distilled off in a water jet vacuum, the residue is taken up in 1000 ml of methylene chloride and washed three times with 500 ml of water each time. The organic phase is dried over sodium sulfate, filtered and concentrated in a water jet vacuum by distilling off the solvent. The residue is dissolved in 500 ml of ethanol, 40 ml of concentrated hydrochloric acid are added and the solvent is distilled off in a water jet vacuum. The residue is stirred with 500 ml of ether, which leads to crystallization. 66 g (39.3% of theory) of 1- (2,4-dichlorophenoxy) -3,3-dimethyl-4-fluoro-1- (imidazol-1-yl) -2-butanone hydrochloride of melting point 91 are obtained -110 ° C.

Herstellung der VorstufeProduction of the preliminary stage

Figure imgb0011
Figure imgb0011

244,6 g (0,88 Mol) rohes 1-(2,4-Dichlorphenoxy)-3,3-dimethyl-4-fluor-2-butanon werden in 700 ml Chloroform gelöst und bei 30°C tropfenweise mit 46 ml Brom so versetzt, daß laufend Entfärbung eintritt. Nach beendeter Zugabe läßt man 30 Minuten nachrühren und engt dann durch Abdestillieren des Chloroforms im Vakuum ein. Man erhält 315 g (100% der Theorie) 1-Brom-1-(2,4-dichlorphenoxy)-3,3-dimethyl-4-fluor-2-butanon als viskoses Öl, das roh weiter umgesetzt worden kann.

Figure imgb0012
244.6 g (0.88 mol) of crude 1- (2,4-dichlorophenoxy) -3,3-dimethyl-4-fluoro-2-butanone are dissolved in 700 ml of chloroform and added dropwise at 30 ° C. with 46 ml of bromine offset so that discoloration occurs continuously. When the addition is complete, the mixture is stirred for 30 minutes and then concentrated by distilling off the chloroform in vacuo. 315 g (100% of theory) of 1-bromo-1- (2,4-dichlorophenoxy) -3,3-dimethyl-4-fluoro-2-butanone are obtained as a viscous oil which can be reacted further raw.
Figure imgb0012

Zu 140 g (1 Mol) Kaliumcarbonat und 163 g (1 Mol) 2,4-Dichlorphenol in 1000 ml Aceton tropft man in der Siedehitze eine Lösung von 197 g (1 Mol) 1-Brom-3,3-dimethyl-4-fluor-2-butanon in 100 ml Aceton: Man läßt 20 Stunden unter Rückfluß rühren, kühlt ab und filtriert. Das Filtrat wird durch Abdestillieren des Acetons im Wasserstrahlvakuum eingeengt. Der Rückstand wird in 500 ml Toluol gelöst, mit 500 ml 10%iger Natronlauge und zweimal mit je 250 ml Wasser gewaschen, über Natriumsulfat getrocknet und durch Abdestillieren des Toluols im Wasserstrahlvakuum eingeengt. Man erhält 244,6 g (88% der Theorie) 1-(2,4-Dichlorphenoxy)-3,3-dimethyl-4-fluor-2-butanon als hochviskoses Öl, das roh weiter umgesetzt werden kann.

Figure imgb0013
A solution of 197 g (1 mol) of 1-bromo-3,3-dimethyl-4- is added dropwise to 140 g (1 mol) of potassium carbonate and 163 g (1 mol) of 2,4-dichlorophenol in 1000 ml of acetone at the boiling point. fluoro-2-butanone in 100 ml acetone: the mixture is stirred under reflux for 20 hours, cooled and filtered. The filtrate is concentrated by distilling off the acetone in a water jet vacuum. The residue is dissolved in 500 ml of toluene, washed with 500 ml of 10% sodium hydroxide solution and twice with 250 ml of water each time, dried over sodium sulfate and concentrated by distilling off the toluene in a water jet vacuum. 244.6 g (88% of theory) of 1- (2,4-dichlorophenoxy) -3,3-dimethyl-4-fluoro-2-butanone are obtained as a highly viscous oil which can be reacted crude.
Figure imgb0013

118 g (1 Mol) 3,3-Dimethyl-4-fluor-2-butanon werden in 600 ml Chloroform gelöst und tropfenweise so mit 52 ml Brom versetzt, daß laufend Entfärbung eintritt. Nach beendeter Zugabe läßt man 30 Minuten weiterrühren. Danach wird durch Abdestillieren des Lösungsmittels im Vakuum eingeengt. Man erhält 197g (100% der Theorie) 1-Brom-3,3-dimethyl-4-fiuor-2-butanon vom Siedepunkt 85-90°C/12 mm Hg-Säule, das roh weiter umgesetzt werden kann.

Figure imgb0014
118 g (1 mol) of 3,3-dimethyl-4-fluoro-2-butanone are dissolved in 600 ml of chloroform and 52 ml of bromine are added dropwise in such a way that decolorization occurs continuously. After the addition has ended, stirring is continued for 30 minutes. It is then concentrated by distilling off the solvent in vacuo. This gives 197 g (100% of theory) of 1-bromo-3,3-dimethyl-4-fiuor-2-butanone with a boiling point of 85-90 ° C./12 mm Hg column, which can be further reacted raw.
Figure imgb0014

Zu der in einem Dreihals-Rührkolben mit absteigendem Kühler befindlichen Suspension von 23,2 g (0,4 Mol) trockenem Kaliumfluorid in 400 ml dest. Tetraethylenglykol werden bei 160°C und 20 mbar 38,8 g (0,2 Mol) 2,2-Dimethyl-2-oxobutyl-methansulfonat im Verlauf von 2 Stunden zugetropft und 2 weitere Stunden nachgerührt. An einem absteigenden Kondensator und in einer nachgeschalteten Tiefkühlfalle wird das herausdestillierte Reaktionsprodukt kondensiert und gesammelt. Man erhält 20,9% (89% der Theorie) 3,3-Dimethyl-4-fluor-2-butanon, vom Siedepunkt 130 -134° C.

Figure imgb0015
To the suspension of 23.2 g (0.4 mol) of dry potassium fluoride in 400 ml dist. In a three-neck stirred flask with a descending condenser. Tetraethylene glycol is added dropwise at 160 ° C. and 20 mbar, 38.8 g (0.2 mol) of 2,2-dimethyl-2-oxobutyl methanesulfonate over the course of 2 hours and the mixture is stirred for a further 2 hours. The distilled reaction product is condensed and collected on a descending condenser and in a downstream freezer trap. 20.9% (89% of theory) of 3,3-dimethyl-4-fluoro-2-butanone are obtained, with a boiling point of 130 ° -134 ° C.
Figure imgb0015

232 g (2 Mol) 3,3-Dimethyl-4-hydroxy-2-butanon (z. Herstellung vgl. Beilstein, H 1 E III 3239, IV, 4030, und Bull. Soc. Chim. France, 1964, 2849) werden in 700 ml absolutem Pyridin bei 0 bis 5°C mit 229 g (2 Mol) Methansulfochlorid umgesetzt. Nach 12 Stunden Stehen bei 20°C wird mit Methylenchlorid verdünnt und mit Eiswasser ausgeschüttelt. Die organische Phase wird getrocknet, im Vakuum vom Lösungsmittel befreit und über eine Kolonne fraktioniert. Man erhält 332 g (86% der Theorie) 2,2-Dimethyl-3-oxo-butyl-methansulfonatvom Siedepunkt 106-120°C/0,12 mm Hg-Säule.232 g (2 mol) of 3,3-dimethyl-4-hydroxy-2-butanone (for preparation see Beilstein, H 1 E III 3239, IV, 4030, and Bull. Soc. Chim. France, 1964, 2849) are reacted in 700 ml of absolute pyridine at 0 to 5 ° C with 229 g (2 mol) of methanesulfonyl chloride. After standing at 20 ° C. for 12 hours, the mixture is diluted with methylene chloride and shaken out with ice water. The organic phase is dried, freed from the solvent in vacuo and fractionated over a column. 332 g (86% of theory) of 2,2-dimethyl-3-oxo-butyl methanesulfonate with a boiling point of 106-120 ° C / 0.12 mm Hg column are obtained.

Beispiel 2Example 2

Figure imgb0016
Figure imgb0016

44 g (0,1275 Mol) 1-(2,4-Dichlorphenoxy)-3,3-dimethyl-4-fluor-1-(imidazol-1-yl)-2-butanon (Beispiel ) werden in 300 ml Methanol gelöst und bei 0 bis 5°C mit 6,3 g Natriumborhydrid versetzt. Man läßt 15 tunden bei Raumtemperatur nachrühren, tropft 60 ml konzentrierte Salzsäure unter Eiskühlung zu, errührt 10 Stunden bei Raumtemperatur und destilliert das Lösungsmittel im Wasserstrahlvakuum ab. er Rückstand wird in 250 ml Methylenchlorid aufgenommen, in 500 ml wäßrige, gesättigte Natriumhydrogencarbonatlösung eingerührt, die Methylenchloridphase abgetrennt, dreimal mit je 100 ml Wasser gewaschen, die organische Phase über Natriumsulfat getrocknet und das Lösungsmittel abdestilliert. Das zurückbleibende Öl wird in 200 ml Ether aufgenommen, 50 ml' etherische Salzsäure zugegeben und das Lösungsmittel abdestilliert. Man erhält 28,2 g (58% der Theorie) 1-(2,4-Dichlorphenoxy)-3,3-dimethyl-4-fluor-1-(imidazol-1-yl)-2-butanol-hydrochlorid vom Schmelzpunkt 184-210°C als Diastereomerengemisch.44 g (0.1275 mol) of 1- (2,4-dichlorophenoxy) -3,3-dimethyl-4-fluoro-1- (imidazol-1-yl) -2-butanone (example) are dissolved in 300 ml of methanol and at 0 to 5 ° C with 6.3 g of sodium borohydride. The mixture is left to stir at room temperature for 15 hours, 60 ml of concentrated hydrochloric acid are added dropwise with ice cooling, the mixture is stirred at room temperature for 10 hours and the solvent is distilled off in a water jet vacuum. he residue is taken up in 250 ml of methylene chloride, in 500 ml of saturated aqueous Sodium bicarbonate solution stirred in, the methylene chloride phase separated, washed three times with 100 ml of water, the organic phase dried over sodium sulfate and the solvent distilled off. The remaining oil is taken up in 200 ml of ether, 50 ml of ethereal hydrochloric acid are added and the solvent is distilled off. 28.2 g (58% of theory) of 1- (2,4-dichlorophenoxy) -3,3-dimethyl-4-fluoro-1- (imidazol-1-yl) -2-butanol hydrochloride of melting point 184 are obtained -210 ° C as a mixture of diastereomers.

Beispiel 3Example 3

Figure imgb0017
Figure imgb0017

61,5 g (0,18 Mol) 3,3-Bisfluormethyl-1-brom-1-(4-chlorphenoxy)-butan-2-on werden mit 27,2 g (0,4 Mol) Imidazol in 500 ml Acetonitril 4 Stunden bei 45°C gerührt. Das Lösungsmittel wird im Wasserstrahlvakuum abdestilliert, das zurückbleibende Öl in 500 ml Methylenchlorid aufgenommen, die organische Phase zweimal mit 1000 ml Wasser gewaschen, über Natriumsulfat getrocknet und das Lösungsmittel abdestilliert. Das Öl wird in Aceton aufgenommen, mit 36 g (0,1 Mol) 1,5-Naphthalindisulfonsäure-tetrahydrat versetzt und der entstehende Niederschlag abgesaugt. Der Niederschlag (das 1,5-Naphthalindisulfonat des eispiels 3) wird mit Natriumhydrogencarbonatlösung behandelt. Man erhält 14 g (24% der Theorie) 3,3-Bisfluormethyl-1-(4-chlorphenoxy)-1-(imidazol-1-yl)-butan-2-on als zähflüssiges Öl.61.5 g (0.18 mol) of 3,3-bisfluoromethyl-1-bromo-1- (4-chlorophenoxy) butan-2-one are mixed with 27.2 g (0.4 mol) of imidazole in 500 ml of acetonitrile Stirred at 45 ° C for 4 hours. The solvent is distilled off in a water jet vacuum, the remaining oil is taken up in 500 ml of methylene chloride, the organic phase is washed twice with 1000 ml of water, dried over sodium sulfate and the solvent is distilled off. The oil is taken up in acetone, 36 g (0.1 mol) of 1,5-naphthalenedisulfonic acid tetrahydrate are added and the resulting precipitate is filtered off with suction. The precipitate (the 1,5-naphthalene disulfonate of Example 3) is treated with sodium bicarbonate solution. 14 g (24% of theory) of 3,3-bisfluoromethyl-1- (4-chlorophenoxy) -1- (imidazol-1-yl) -butan-2-one are obtained as a viscous oil.

Herstellung der VorstufenProduction of the preliminary stages

Figure imgb0018
Figure imgb0018

Entsprechend Beispiel 1 durch Umsetzung von 3,3-Bis-fluormethyl-1-(4-chlorphenoxy)-butan-2-on mit Brom.

Figure imgb0019
According to Example 1 by reacting 3,3-bis-fluoromethyl-1- (4-chlorophenoxy) butan-2-one with bromine.
Figure imgb0019

Entsprechend Beispiel 1 durch Umsetzung von 3,3-Bisfluormethyl-butan-2-on mit Brom.

Figure imgb0020
According to Example 1 by reacting 3,3-bisfluoromethyl-butan-2-one with bromine.
Figure imgb0020

In einem Dreihalskolben mit Rührer, Tropftrichter und Liebigkühler mit gekühlter Vorlage werden 400 ml Tetraethylenglykol und 46.4 g Kaliumfluorid (0,8 Mol) vorgelegt und auf 170° C aufgeheizt. Man legt an den Vorstoß des Liebigkühlers ein Wasserstrahlvakuum (Druck ca. 20 bis 30 mbar) an. Dann werden während 45 Minuten 57,6 g (0,2 Mol) 2-Acetyl-2-methyl-propan-1,3-diol-bismethansulfat, gelöst in 100 ml Tetraethylenglykol, zugetropft. Das entstehende 3,3-Bisfluormethyl-butan-2-on wird während der Reaktion in die gekühlte Vorlage abdestilliert. Nach dem Zutropfen wird noch während 1 Stunde bei 175° C weiter destilliert.400 ml of tetraethylene glycol and 46.4 g of potassium fluoride (0.8 mol) are placed in a three-necked flask equipped with a stirrer, dropping funnel and Liebig cooler with a cooled receiver and heated to 170.degree. A water jet vacuum (pressure approx. 20 to 30 mbar) is applied to the advance of the Liebig cooler. Then 57.6 g (0.2 mol) of 2-acetyl-2-methyl-propane-1,3-diol-bismethanesulfate, dissolved in 100 ml of tetraethylene glycol, are added dropwise over 45 minutes. The resulting 3,3-bisfluoromethyl-butan-2-one is distilled off into the cooled receiver during the reaction. After the dropwise addition, distillation is continued at 175 ° C. for 1 hour.

Das aufgefangene Destillat wird anschließend redestilliert. Man erhält 14 g (ca. 51,5% der Theorie) 3,3-Bisfluormethyl-butan-2-on vom Siedepunkt 43-46°C/12 mm Hg-Säule.

Figure imgb0021
The distillate collected is then redistilled. 14 g (approx. 51.5% of theory) of 3,3-bisfluoromethyl-butan-2-one with a boiling point of 43-46 ° C./12 mm Hg column are obtained.
Figure imgb0021

66 g (0,5 Mol) 3-Oxa-2,2-bis-(hydroxymethyl)-butan (zur Herstellung vgl. Beilstein, H 1, E III 3306, IV, 4132, und J. Chem. Soc., London, 1932,2671) werden in 300 ml1,2-Dichlorethan gelöst, 114,5 g (1 Mol) Methansulfonsäurechlorid zugetropft und bei 0 bis 5°C 158 g (2 Mol) Pyridin zugetropft. Man läßt 15 Stunden bei Raumtemperatur nachrühren und gibt den Ansatz auf 600 ml Eiswasser und 100 ml konz. Salzsäure. Dabei fällt ein Feststoff aus, der abgesaugt wird. Die wäßrige Phase wird mit 1000 ml Methylenchlorid extrahiert; in der Methylenchloridphase wird der Feststoff gelöst, die organische Phase über Natriumsulfat getrocknet, das Lösungsmittel im Wasserstrahlvakuum abdestilliert und der Rückstand in 200 ml Ether suspendiert. Der Rückstand wird abgesaugt und mit 100 ml Ether gewaschen.66 g (0.5 mol) of 3-oxa-2,2-bis (hydroxymethyl) butane (for the preparation see Beilstein, H 1, E III 3306, IV, 4132, and J. Chem. Soc., London , 1932.2671) are dissolved in 300 ml of 1,2-dichloroethane, 114.5 g (1 mol) of methanesulfonyl chloride are added dropwise and 158 g (2 mol) of pyridine are added dropwise at 0 to 5 ° C. The mixture is stirred for 15 hours at room temperature and the mixture is poured onto 600 ml of ice water and 100 ml of conc. Hydrochloric acid. A solid precipitates, which is suctioned off. The aqueous phase is extracted with 1000 ml of methylene chloride; the solid is dissolved in the methylene chloride phase, the organic phase is dried over sodium sulfate, the solvent is distilled off in a water jet vacuum and the residue is suspended in 200 ml of ether. The residue is filtered off and washed with 100 ml of ether.

Man erhält 100 g (ca. 70% der Theorie) 2-Acetyl-2-methyl-propan-1,3-diol-bis-methansulfonat vom Schmelzpunkt 105 bis 108° C.100 g (about 70% of theory) of 2-acetyl-2-methyl-propane-1,3-diol-bis-methanesulfonate with a melting point of 105 to 108 ° C. are obtained.

In entsprechender Weise werden die nachfolgenden Beispiele der allgemeinen Formel I

Figure imgb0022
erhalten:
Figure imgb0023
Figure imgb0024
 The following examples of the general formula I
Figure imgb0022
 receive:
Figure imgb0023
Figure imgb0024

Claims (9)

1. Antimycotic agent, characterised in that it contains at least one fluorinated 1-imidazolyl-butane lerivative of the general formula I
Figure imgb0026
n which
I represents the keto group or the CH(OH)-grouping,
represents hydrogen or fluorine,
Z represents halogen, alkyl with 1 to 4 carbon atoms, nitro, cyano, alkoxycarbonyl with 1 to 4 carbon atoms in the alkyl part, or phenyl which is optionally substituted by halogen, and
n represents 0,1,2 or 3,

and/or physiologically acceptable acid addition salts and/or metal complexes thereof.
2. Antimycotic agent according to Claim 1, characterised in that it contains at least one fluorinated 1-imidazolyl-butane derivative of the general formula 1 in Claim 1, in which
Z represents halogen, methyl, ethyl, nitro, cyano, methoxycarbonyl, ethoxycarbonyl, phenyl or chlorophenyl,
n represents 0, 1 or 2 and
B and X habe the meaning given above.
3. Antimycotic agent according to Claim 1, characterised in that it contains 1-(2,4-dichlorophen- oxy)-3,3-dimethyl-4-fluoro-1-(imidazol-1-yl)-2-butanone.
4. Antimycotic agent according to Claim 1, characterised in that it contains 1-(4-chlorophenoxy)-3,3-di-(fluoromethyl)-1-(imidazol-1-yl)-2-butanone.
5. Antimycotic agent according to Claim 1, characterised in that it contains 1-(4-fluorophenoxy)-3,3-di-(fluoromethyl)-1-(imidazol-1-yl)-2-butanone.
6. Antimycotic agent according to Claim 1, characterised in that it contains 1-(4-chlorophenoxy)-3,3-dimethyl-4-fluoro-1-(imidazol-1-yl)-2-butanol.
7. Antimycotic agent according to Claim 1, characterised in that it contains 1-(4-bromophenoxy)-3,3-dimethyl-4-fluoro-1-(imidazol-1-yl)-2-butanol.
8. Process for the preparation of an antimycotic agent according to Claim 1, characterised in that fluorinated 1-imidazolyl-butane derivatives according to the general formula I in Claim 1 are mixed with inert, non-toxic, pharmaceutically suitable excipients.
EP80102288A 1979-05-10 1980-04-28 Antimycotic agent, process for its preparation Expired EP0019730B1 (en)

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